Renal Fibrosis Reduced in Mouse Model Using Drugs That Block Wnt Secretion

Renal Fibrosis Reduced in Mouse Model Using Drugs That Block Wnt Secretion

Chronic kidney injury results in progressive scarring known as renal fibrosis. But drugs that target Wnt secretion by inhibiting Porcupine, a protein commonly targeted to treat different cancers, may be a treatment option for renal fibrosis and help to protect the kidneys.

The study, “Experimental inhibition of porcupine-mediated Wnt O-acylation attenuates kidney fibrosis,” was published in the journal Kidney International.

Renal fibrosis is a final common pathway for both immune-mediated glomerulonephritides and kidney diseases initiated by hemodynamic insults, such as hypertension. The extent of fibrosis is a predictor of the progression to end-stage kidney disease in most forms of chronic kidney disease. Despite research efforts, there currently are no therapies to abrogate or reverse fibrosis in individuals with chronic kidney disease.

In recent years, the Wingless-related integration site (Wnt) family of signaling proteins has emerged as a potential target of inhibitors to control fibrosis in several organs.

Babita Madan and David Virshup, both professors at Duke-NUS Medical School in Singapore, and Steven Crowley, an associate professor from Duke University in North Carolina, used a mouse model of kidney fibrosis to investigate if Wnt secretion inhibitors could treat fibrosis. These drugs are also being explored as treatment options for certain cancers.

Researchers blocked one ureter to damage and scar the affected kidney in mice, and found that restraining Wnt secretion interrupted the build-up of scar tissue there. Specifically, the team found that preventing the secretion of Wnt using the PORCN inhibitor C59 blunts the proliferation of fibroblasts and the expression of key pro-inflammatory cytokines that are, in turn, capable of eliciting Wnt generation.

The results provide the basis for a new therapeutic approach to protect the kidney from becoming fibrotic (scarring), and provide a basis to assess the use of Wnt secretion inhibitors as a treatment option for kidney as well as other fibrotic disorders.

“This is the first study to demonstrate that a Wnt secretion inhibitor can be useful for preventing renal fibrosis,” Dr. Madan, the study’s first author, said in a news release. “There could be potential long-term therapeutic treatments that could arise from this new knowledge, which can be explored for the treatment of additional fibrotic disorders including kidney disease.”

Dr. Virshup, director of the Cancer and Stem Cell Biology Programme at Duke-NUS, and Dr. Madan, in partnership with A*STAR’s Experimental Therapeutics Centre (ETC), have advanced a drug called ETC-159, a Wnt secretion inhibitor currently in Phase 1 clinical testing as a cancer treatment.

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